TCIRG1

TCIRG1
Identifiers
Aliases	TCIRG1, ATP6N1C, ATP6V0A3, Atp6i, OC-116kDa, OC116, OPTB1, Stv1, TIRC7, Vph1, a3, T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3, T cell immune regulator 1, ATPase H+ transporting V0 subunit a3
External IDs	OMIM: 604592; MGI: 1350931; HomoloGene: 4392; GeneCards: TCIRG1; OMA:TCIRG1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.2 Start 68,039,016 bp[1] End 68,050,895 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 A|19 3.62 cM Start 3,946,050 bp[2] End 3,957,133 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte blood spleen body of pancreas right adrenal cortex left adrenal cortex canal of the cervix gastric mucosa upper lobe of left lung right lung Top expressed in stroma of bone marrow granulocyte body of femur thymus decidua internal carotid artery tibiofemoral joint mesenteric lymph nodes external carotid artery duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transporter activity ATPase binding proton-transporting ATPase activity, rotational mechanism proton transmembrane transporter activity Cellular component integral component of membrane proton-transporting V-type ATPase, V0 domain phagocytic vesicle membrane membrane vacuolar proton-transporting V-type ATPase, V0 domain plasma membrane integral component of plasma membrane lysosomal membrane apical plasma membrane mitochondrion vacuolar proton-transporting V-type ATPase complex endosome membrane ficolin-1-rich granule membrane nucleus lysosome late endosome secretory granule membrane phagocytic vesicle Biological process protein catabolic process in the vacuole insulin receptor signaling pathway transferrin transport vacuolar proton-transporting V-type ATPase complex assembly ion transport vacuolar acidification cellular defense response ion transmembrane transport positive regulation of cell population proliferation ATP synthesis coupled proton transport macroautophagy phagosome acidification neutrophil degranulation transport proton transmembrane transport ossification osteoclast proliferation immunoglobulin production cellular calcium ion homeostasis apoptotic process inflammatory response regulation of proton transport response to silver ion regulation of gene expression immunoglobulin mediated immune response optic nerve development myeloid cell differentiation B cell differentiation T cell differentiation osteoclast differentiation memory T cell activation T-helper 1 cell activation odontogenesis T cell homeostasis tooth eruption bone resorption regulation of osteoblast differentiation pH reduction homeostasis of number of cells regulation of insulin secretion retina development in camera-type eye hematopoietic stem cell homeostasis enamel mineralization cellular response to cytokine stimulus dentin mineralization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10312 27060 Ensembl ENSG00000110719 ENSMUSG00000001750 UniProt Q13488 n/a RefSeq (mRNA) NM_006019 NM_006053 NM_001351059 NM_001136091 NM_001167784 NM_016921 RefSeq (protein) NP_006010 NP_006044 NP_001337988 n/a Location (UCSC) Chr 11: 68.04 – 68.05 Mb Chr 19: 3.95 – 3.96 Mb PubMed search [3] [4]
Wikidata
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The TCIRG1 (T cell immune regulator 1) gene encodes for the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.

Gene

TCIRG1 (T cell immune regulator 1) is a gene that encodes the V-type proton ATPase (V-ATPase) 116 kDa subunit a isoform 3 enzyme.^[5][6][7]

Function

Through alternate splicing, the TCIRG1 gene encodes two protein isoforms with similarity to subunits of the vacuolar ATPase (V-ATPase) but the encoded proteins seem to have different functions. V-ATPase is a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is composed of a cytosolic V₁ domain and a transmembrane V₀ domain.

The two isoforms are:

• long isoform a, also named OC116
• short isoform b, also named TIRC7 (N-terminus truncated, lacks amino acid residues 1-216 of the long isoform)

TIRC7 is expressed in T lymphocytes and is essential for normal T cell activation. This variant uses a transcription start site that is within exon 5 of variant 1 followed by an intron as part of its 5' UTR.

TIRC7

TIRC7 is a 75 kDa membrane protein, first described in 1998, that plays a central role in T cell activation.^[6]

Expression

TIRC7 is induced after immune activation^[6] on the cell surface of certain peripheral human T and B cells as well as monocytes and IL-10 expressing regulatory T cells. During immune activation, TIRC7 is co-localized with the T cell receptor and CTLA4 within the immune synapse of human T cells.^[8][9] At the protein and mRNA level, its expression is induced in lymphocytes in synovial tissues obtained from patients with rheumatoid arthritis^[10][11] or during rejection of solid organ transplants^[12][13][14] and bone marrow transplantation^[15] as well as in brain tissues obtained from patients with multiple sclerosis.^[16][17][18]

Function

Antibody targeting of TIRC7 suppresses T cell activation and IL-2 secretion.^[6] Specifically, significant prevention of inflammation in a variety of animal models has been shown. These include rejection of transplanted kidney and heart allografts^[19][20] as well as progression of arthritis and experimental autoimmune encephalomyelitis (EAE). These effects were accompanied with significant decreases of Th1 specific cytokines e.g. IFN-gamma, TNF-alpha, IL-2 expression and transcription, induction of CTLA4 whereas IL-10 remained unchanged. The induction of TIRC7 in IL-10 secreting T regulatory cells and the prevention of colitis in the presence of TIRC7 positive T regulatory cells^[21] supports the inhibitory signals induced via TIRC7 pathway during immune activation.^[22] Further evidence for the inhibitory role of TIRC7 during the course of immune response is that prevention of colitis was achievable by a transfer of TIRC7 positive cells into CD45RO mice prior to induction of colitis. The negative immune regulatory role of TIRC7 is furthermore supported by the fact that TIRC7 knock out mice exhibits an increased T and B cell response in the presence of various stimuli in vitro and in vivo exhibiting. A significant induced memory cell subset and reduction of CTLA4 expression observed in TIRC7 knock out mice.^[23]

Ligand

The cell surface ligand to TIRC7 is the non-polymorphic alpha 2 domain (HLA-DRα2) of HLA DR protein.^[24] Upon lymphocyte activation TIRC7 is upregulated to engage HLA-DRα2 and induce apoptotic signals in human CD4+ and CD8+ T-cells. The down-regulation of the immune response is achieved via activation of the intrinsic apoptotic pathway by caspase 9, inhibition of lymphocyte proliferation, SHP-1 recruitment, decrease in phosphorylation of STAT4, TCR-ζ chain and ZAP70 as well as inhibition of FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. In vivo, triggering the HLA-DR-TIRC7 pathway in lipopolysaccaride (LPS) activated lymphocytes using soluble HLA-DRα2 leads to inhibition of proinflammatory as well as inflammatory cytokines and induction of apoptosis. These results strongly support the regulatory role of TIRC7 signalling pathway in lymphocytes.

Clinical significance

TCIRG1 mutations affect the a3 subunit of the vacuolar proton pump, which in turn affects the acidification of the bone-osteoclast interface, resulting in infantile malignant osteopetrosis.^[25][26][7]

See also

• T cell
• Co-stimulation
• MHC class II
• CTLA-4
• apoptosis

References

Bibliography

External links

• TCIRG1 human gene location in the UCSC Genome Browser.
• TCIRG1 human gene details in the UCSC Genome Browser.